BIOCHEMICAL CHARACTERIZATION OF OPIOID LIGANDS AND RECEPTORS

治疗与手术、创伤和许多疾病相关的疼痛 疾病状态是医疗实践中必不可少的一部分。 吗啡等阿片类药物仍然是治疗糖尿病最有效的药物 用于治疗剧烈疼痛，并被广泛用于此目的 尽管有许多严重的胃肠道、心血管和 呼吸道副作用。更糟糕的是，这些药物会产生一种 反复使用后身体依赖的状态，可能导致 上瘾。在Delta阿片类药物中起作用的最有效药物 受体是不能进入中枢神经的多肽 传统的给药途径之后的系统。新的 如果化合物要在临床上有用，就必须制成化合物。 这项建议试图回答问题，“能阿片肽 选择Delta受体的配体被分成不同的基团 区别于它们在不同的细胞中结合这种受体的能力 虽然众所周知，这些药物必须与 阿片受体产生镇痛等作用，显著 它们的化学结构的差异强烈地表明 他们必须以不同的方式做到这一点。如果，正如这所暗示的那样， 这些药物与同一受体结合的方式不同， 那么这种差异是如何影响他们的行为方式的呢？毒品 通过与特定受体氨基的接触与受体结合 由DNA编码的酸。我们建议修改 Delta阿片受体具有来自以下来源的氨基酸序列 其他阿片受体(Mu An Kappa)替代现有阿片受体 Delta受体序列。这种人造受体被称为 一种嵌合体，它将具有衍生的药物识别特性 来自两个亲代受体。这样的大尺度 修饰可以用来缩小受体中的位置 毒品是绑在一起的。受体氨基之间的个体接触 药物的酸和官能团可以通过以下方法确定 选择性地改变编码单个氨基酸的DNA序列 采用定点诱变技术。使用 这两个工具我们打算(1)显示化学定义的 阿片类药物的组持续使用特定的组 氨基酸用于Delta受体的结合和(2)即使用 这些不同的“识别站点”负责特定的 这些药物的性质。这些信息可能会带来革命性的变化 新的阿片类药物是如何设计的，因为它定义了这些药物 通过它们与Delta受体的相互作用，而不是通过它们的 化学结构。

The treatment of pain associated with surgery, trauma and many diseases states is an essential part of medical practice. Opinoids such as morphine remain the most effective drugs for the treatment of severe pain and are widely used for this purpose despite haveing many serious gastrointestinal, cardiovascular and respiratory side effects. Worst still, these drugs produce a state of physical dependence after repeated use that can lead to addiction. The most effective drugs acting at delta opioid receptors are peptides that cannot enter the central nervous system after conventional routes of administration. New compounds must be made if they are to be useful in the clinic. This proposal seeks to answer the questin, "Can opioid peptide ligands selective for the delta receptor be divided into groups distinguished by their ability to bind this receptor in different ways?" While it is well understood that these drugs must bind opioid receptors to produce effects such as analgesia, marked differences in their chemical structures strongly suggest that they must do so in different ways. If, as this implies, there are different ways for these drugs to bind to the same receptor, then how does this difference affect the way they act? Drugs bind to receptors through contacts with specific receptor amino acids that are in turn encoded by DNA. We propose to modify delta opioid receptors to have amino acid sequences obtained from other opioid receptors (mu an kappa) substituted for existing delta receptor sequences. Such an artificial receptor is called a chimera and it would have drug recognition properties derived from both parent receptors. This kind of large scale modification can be used to narrow down where in the receptor drugs are bound. Individual contacts between receptor amino acids and functional groups of a drug can be determined by selectively changing the DNA sequence encoding a single amino acid using the technique of site-directed mutagenesis. With these two tools we intend to (1) show that chemically defined groups of opioid drugs consistently use particular groups of aiminoacids for delta receptor binding and (2) that the use of these different "recognition sites" is responsible for specific properties of these drugs. This information could revolutionize how new opioid drugs are designed since it defines these drugs by how they interact with delta receptors rather than by their chemical structures.